title: Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial.
abstract: OBJECTIVE
  To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy.
  
  
  BACKGROUND
  One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI.
  
  
  METHODS
  We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio.
  
  
  RESULTS
  Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin-creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P=0.1).
  
  
  CONCLUSIONS
  In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.
authors.affiliation: *Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University of Belfast, Belfast, Ireland †Department of Anaesthesia, Royal Victoria Hospital, Belfast, Ireland ‡Department of Cardio-Thoracic Surgery, Royal Victoria Hospital, Belfast, Ireland §Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland ‖Cardiovascular Research Institute, University of California, San Francisco, CA ¶National Heart and Lung Institute, Royal Brompton Hospital, London; and **Clinicial Research Support Centre, Royal Hospitals, Belfast, UK.
authors.forename: Murali
authors.initials: M
authors.lastname: Shyamsundar
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.forename: Martin O
authors.initials: MO
authors.lastname: Shields
authors.forename: Rob
authors.initials: R
authors.lastname: MacSweeney
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: Julian R
authors.initials: JR
authors.lastname: Johnston
authors.forename: Jim
authors.initials: J
authors.lastname: McGuigan
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.forename: Michael M
authors.initials: MM
authors.lastname: Matthay
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Griffiths
authors.forename: Cliona
authors.initials: C
authors.lastname: McDowell
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Elborn
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: OʼKane
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000517:prevention & control*; D000368:Aged; D004311:Double-Blind Method; D004727:Endothelium / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000601:surgery*; D016629:Esophagectomy / Q000009:adverse effects*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin